Y-26763: ATP-sensitive K+ channel activation and the inhibition of insulin release from human pancreatic β-cells

The effect of Y-26763 [(-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4- dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol], a novel ATP-sensitive K+ (KATP) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose- and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic β-cells which express KATP channels comprised of Kir6.2 and SUR1, and the NES2Y human β-cell line, transfected with Kir6.2ΔC26. Y-26763 activated KATP channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2ΔC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of KATP channels in human β-cells. © 2004 Elsevier B.V. All rights reserved.